CERN-based experiments and Monte-Carlo studies on focused dose delivery with very high energy electron (VHEE) beams for radiotherapy applications.

Very High Energy Electron (VHEE) beams are a promising alternative to conventional radiotherapy due to their highly penetrating nature and their applicability as a modality for FLASH (ultra-high dose-rate) radiotherapy. The dose distributions due to VHEE need to be optimised; one option is through the use of quadrupole magnets to focus the beam, reducing the dose to healthy tissue and allowing for targeted dose delivery at conventional or FLASH dose-rates. This paper presents an in depth exploration of the focusing achievable at the current CLEAR (CERN Linear Electron Accelerator for Research) facility, for beam energies >200 MeV. A shorter, more optimal quadrupole setup was also investigated using the TOPAS code in Monte Carlo simulations, with dimensions and beam parameters more appropriate to a clinical situation. This work provides insight into how a focused VHEE radiotherapy beam delivery system might be achieved.

Characterisation of the UK high energy proton research beamline for high and ultra-high dose rate (FLASH) irradiation.

Objective. This work sets out the capabilities of the high energy proton research beamline developed in the Christie proton therapy centre for Ultra-High Dose Rate (UHDR) irradiation and FLASH experiments. It also characterises the lower limits of UHDR operation for this Pencil Beam Scanning (PBS) proton hardware.Approach. Energy dependent nozzle transmission was measured using a Faraday Cup beam collector. Spot size was measured at the reference plane using a 2D scintillation detector. Integrated depth doses (IDDs) were measured. EBT3 Gafchromic film was used to compare UHDR and conventional dose rate spots. Our beam monitor calibration methodolgy for UHDR is described. A microDiamond detector was used to determine dose rates at zref. Instantaneous depth dose rates were calculated for 70-245 MeV. PBS dose rate distributions were calculated using Folkerts and Van der Water definitions.Main results. Transmission of 7.05 ± 0.1% is achieveable corresponding to a peak instantaneous dose rate of 112.7 Gy s-1. Beam parameters are comparable in conventional and UHDR mode with a spot size ofσx= 4.6 mm,σy= 6.6 mm. Dead time in the beam monitoring electonics warrants a beam current dependent MU correction in the present configuration. Fast beam scanning of 26.4 m s-1(X) and 12.1 m s-1(Y) allows PBS dose rates of the order tens of Grays per second.Significance. UHDR delivery is possible for small field sizes and high energies enabling research into the FLASH effect with PBS protons at our facility. To our knowledge this is also the first thorough characterisation of UHDR irradiation using the hardware of this clinical accelerator at energies less than 250 MeV. The data set out in this publication can be used for designing experiments at this UK research facility and inform the possible future clinical translation of UHDR PBS proton therapy.

Barriers and facilitators to conducting radiotherapy clinical trials: Findings from a UK survey.

INTRODUCTION: As an essential component of service delivery, radiotherapy clinical trials were championed within the NHS England service specifications. A call for a 15% increase in research and clinical trial activity, alongside a demand for equity of access for patients with cancer subsequently ensued. National understanding of current radiotherapy clinical trials operational practices is absent, but essential to help establish the current provision required to support the development of a strategic plan for implementation of NHS England's specifications. METHODS: A cross-sectional survey was developed by a multi-disciplinary team and distributed to therapeutic radiography clinical trial leads across the UK to ascertain the current provision of radiotherapy clinical trials only, including workforce resources and the trials management processes to establish a benchmark and identify potential barriers, enablers, and opportunities to increase access to clinical trials. RESULTS: Thirty-two complete responses were obtained equating to 49% of the total UK NHS departments and 74% of those departments invited. Four key findings were identified: 1) research strategy and systems, 2) participation and activity in radiotherapy clinical trials, 3) access to clinical trials at alternative departments and 4) facilitators & barriers. Overarchingly a lack of radiotherapy clinical trials strategy or supported processes were apparent across the UK, aggravating existing barriers to trial activity. CONCLUSION: It is essential for radiotherapy clinical trials to be embedded in to departmental and Trust strategy, this will help to ensure the processes and resources required for trial delivery are not only in place, but also recognised as imperative and important for patients with cancer as radiotherapy treatment delivery. IMPLICATIONS FOR PRACTICE: Failure to address the barriers or build upon the facilitators may result in UK radiotherapy departments facing challenges in achieving the 15% increase in radiotherapy clinical trial activity.

Focused VHEE (very high energy electron) beams and dose delivery for radiotherapy applications.

This paper presents the first demonstration of deeply penetrating dose delivery using focused very high energy electron (VHEE) beams using quadrupole magnets in Monte Carlo simulations. We show that the focal point is readily modified by linearly changing the quadrupole magnet strength only. We also present a weighted sum of focused electron beams to form a spread-out electron peak (SOEP) over a target region. This has a significantly reduced entrance dose compared to a proton-based spread-out Bragg peak (SOBP). Very high energy electron (VHEE) beams are an exciting prospect in external beam radiotherapy. VHEEs are less sensitive to inhomogeneities than proton and photon beams, have a deep dose reach and could potentially be used to deliver FLASH radiotherapy. The dose distributions of unfocused VHEE produce high entrance and exit doses compared to other radiotherapy modalities unless focusing is employed, and in this case the entrance dose is considerably improved over existing radiations. We have investigated both symmetric and asymmetric focusing as well as focusing with a range of beam energies.

Inference of dominant modes for linear stochastic processes.

For dynamical systems that can be modelled as asymptotically stable linear systems forced by Gaussian noise, this paper develops methods to infer (estimate) their dominant modes from observations in real time. The modes can be real or complex. For a real mode (monotone decay), the goal is to infer its damping rate and mode shape. For a complex mode (oscillatory decay), the goal is to infer its frequency, damping rate and (complex) mode shape. Their amplitudes and correlations are encoded in a mode covariance matrix that is also to be inferred. The work is motivated and illustrated by the problem of detection of oscillations in power flow in AC electrical networks. Suggestions of some other applications are given.

Determining the parameter space for effective oxygen depletion for FLASH radiation therapy.

There has been a recent revival of interest in the FLASH effect, after experiments have shown normal tissue sparing capabilities of ultra-high-dose-rate radiation with no compromise on tumour growth restraint. A model has been developed to investigate the relative importance of a number of fundamental parameters considered to be involved in the oxygen depletion paradigm of induced radioresistance. An example eight-dimensional parameter space demonstrates the conditions under which radiation may induce sufficient depletion of oxygen for a diffusion-limited hypoxic cellular response. Initial results support experimental evidence that FLASH sparing is only achieved for dose rates on the order of tens of Gy s-1or higher, for a sufficiently high dose, and only for tissue that is slightly hypoxic at the time of radiation. We show that the FLASH effect is the result of a number of biological, radiochemical and delivery parameters. Also, the threshold dose for a FLASH effect occurring would be more prominent when the parameterisation was optimised to produce the maximum effect. The model provides a framework for further FLASH-related investigation and experimental design. An understanding of the mechanistic interactions producing an optimised FLASH effect is essential for its translation into clinical practice.

Inter- and intra-fractional stability of rectal gas in pelvic cancer patients during MRIgRT.

PURPOSE: Due to the electron return effect (ERE) during magnetic resonance imaging guided radiotherapy (MRIgRT), rectal gas during pelvic treatments can result in hot spots of over-dosage in the rectal wall. Determining the clinical impact of this effect on rectal toxicity requires estimation of the amount and mobility (and stability) of rectal gas during treatment. We therefore investigated the amount of rectal gas and local inter- and intra-fractional changes of rectal gas in pelvic cancer patients. METHODS: To estimate the volume of gas present at treatment planning, the rectal gas contents in the planning computed tomography (CT) scans of 124 bladder, 70 cervical and 2180 prostate cancer patients were calculated. To estimate inter- and intra-fractional variations in rectal gas, 174 and 131 T2-w MRIs for six cervical and eleven bladder cancer patients were used. These scans were acquired during four scan-sessions (~20-25 min each) at various time-points. Additionally, 258 T2-w MRIs of the first five prostate cancer patients treated using MRIgRT at our center, acquired during each fraction, were analyzed. Rectums were delineated on all scans. The area of gas within the rectum delineations was identified on each MRI slice using thresholding techniques. The area of gas on each slice of the rectum was used to calculate the inter- and intra-fractional group mean, systematic and random variations along the length of the rectum. The cumulative dose perturbation as a result of the gas was estimated. Two approaches were explored: accounting or not accounting for the gas at the start of the scan-session. RESULTS: Intra-fractional variations in rectal gas are small compared to the absolute volume of rectal gas detected for all patient groups. That is, rectal gas is likely to remain stable for periods of 20-25 min. Larger volumes of gas and larger variations in gas volume were observed in bladder cancer patients compared with cervical and prostate cancer patients. For all patients, local cumulative dose perturbations per beam over an entire treatment in the order of 60 % were estimated when gas had not been accounted for in the daily adaption. The calculated dose perturbation over the whole treatment was dramatically reduced in all patients when accounting for the gas in the daily set-up image. CONCLUSION: Rectal gas in pelvic cancer patients is likely to remain stable over the course of an MRIgRT fraction, and also likely to reappear in the same location in multiple fractions, and can therefore result in clinically relevant over-dosage in the rectal wall. The over-dosage is reduced when accounting for gas in the daily adaption.

How directed is a directed network?

The trophic levels of nodes in directed networks can reveal their functional properties. Moreover, the trophic coherence of a network, defined in terms of trophic levels, is related to properties such as cycle structure, stability and percolation. The standard definition of trophic levels, however, borrowed from ecology, suffers from drawbacks such as requiring basal nodes, which limit its applicability. Here we propose simple improved definitions of trophic levels and coherence that can be computed on any directed network. We demonstrate how the method can identify node function in examples including ecosystems, supply chain networks, gene expression and global language networks. We also explore how trophic levels and coherence relate to other topological properties, such as non-normality and cycle structure, and show that our method reveals the extent to which the edges in a directed network are aligned in a global direction.

Use of Stokes' theorem for plasma confinement.

Stokes' theorem, in its original form and Cartan's generalization, is crucial for designing magnetic fields to confine plasma (ionized gas). The paper illustrates its use, in particular to address the question whether quasi-symmetric fields, those for which guiding-centre motion is integrable, can be made with little or no toroidal current. This article is part of the theme issue 'Stokes at 200 (Part 1)'.

Experimental verification the electron return effect around spherical air cavities for the MR-Linac using Monte Carlo calculation.

PURPOSE: Dose deposition around unplanned air cavities during magnetic resonance-guided radiotherapy (MRgRT) is influenced by the electron return effect (ERE). This is clinically relevant for gas forming close to or inside organs at risk (OARs) that lie in the path of a single beam, for example, intestinal track during pelvic treatment. This work aims to verify Monte Carlo calculations that predict the dosimetric effects of ERE around air cavities. For this, we use GafChromic EBT3 film inside poly-methyl methacrylate (PMMA) -air phantoms. METHOD: Four PMMA phantoms were produced. Three of the phantoms contained centrally located spherical air cavities (0.5, 3.5, 7.5 cm diameter), and one phantom contained no air. The phantoms were split to sandwich GafChromic EBT3 film in the center. The phantoms were irradiated on an Elekta Unity system using a single 10 × 10 cm2 7-MV photon beam under the influence of a 1.5-T transverse magnetic field. The measurements were replicated using the Elekta Monaco treatment planning system (TPS). Gamma analysis with pass criteria 3%/3 mm was used to compare the measured and calculated dose distributions. We also consider 3%/2 mm, 2%/3 mm, and 2%/2 mm pass criteria for interest. RESULTS: The gamma analysis showed that >95% of the points agreed between the TPS-calculated and measured dose distributions, using 3%/3 mm criteria. The phantom containing the largest air cavity had the lowest agreement, with most of the disagreeing points lying inside the air cavity (dose to air region). CONCLUSIONS: The dose effects due to ERE around spherical air cavities are being calculated in the TPS with sufficient accuracy for clinical use.

In Silico Models of DNA Damage and Repair in Proton Treatment Planning: A Proof of Concept.

There is strong in vitro cell survival evidence that the relative biological effectiveness (RBE) of protons is variable, with dependence on factors such as linear energy transfer (LET) and dose. This is coupled with the growing in vivo evidence, from post-treatment image change analysis, of a variable RBE. Despite this, a constant RBE of 1.1 is still applied as a standard in proton therapy. However, there is a building clinical interest in incorporating a variable RBE. Recently, correlations summarising Monte Carlo-based mechanistic models of DNA damage and repair with absorbed dose and LET have been published as the Manchester mechanistic (MM) model. These correlations offer an alternative path to variable RBE compared to the more standard phenomenological models. In this proof of concept work, these correlations have been extended to acquire RBE-weighted dose distributions and calculated, along with other RBE models, on a treatment plan. The phenomenological and mechanistic models for RBE have been shown to produce comparable results with some differences in magnitude and relative distribution. The mechanistic model found a large RBE for misrepair, which phenomenological models are unable to do. The potential of the MM model to predict multiple endpoints presents a clear advantage over phenomenological models.

Using telematics data to find risky driver behaviour.

Usage-based insurance schemes provide new opportunities for insurers to accurately price and manage risk. These schemes have the potential to better identify risky drivers which not only allows insurance companies to better price their products but it allows drivers to modify their behaviour to make roads safer and driving more efficient. However, for Usage-based insurance products, we need to better understand how driver behaviours influence the risk of a crash or an insurance claim. In this article, we present our analysis of automotive telematics data from over 28 million trips. We use a case control methodology to study the relationship between crash drivers and crash-free drivers and introduce an innovative method for determining control (crash-free) drivers. We fit a logistic regression model to our data and found that speeding was the most important driver behaviour linking driver behaviour to crash risk.

Mechanistic modelling supports entwined rather than exclusively competitive DNA double-strand break repair pathway.

Following radiation induced DNA damage, several repair pathways are activated to help preserve genome integrity. Double Strand Breaks (DSBs), which are highly toxic, have specified repair pathways to address them. The main repair pathways used to resolve DSBs are Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). Cell cycle phase determines the availability of HR, but the repair choice between pathways in the G2 phases where both HR and NHEJ can operate is not clearly understood. This study compares several in silico models of repair choice to experimental data published in the literature, each model representing a different possible scenario describing how repair choice takes place. Competitive only scenarios, where initial protein recruitment determines repair choice, are unable to fit the literature data. In contrast, the scenario which uses a more entwined relationship between NHEJ and HR, incorporating protein co-localisation and RNF138-dependent removal of the Ku/DNA-PK complex, is better able to predict levels of repair similar to the experimental data. Furthermore, this study concludes that co-localisation of the Mre11-Rad50-Nbs1 (MRN) complexes, with initial NHEJ proteins must be modeled to accurately depict repair choice.

Clinically relevant nanodosimetric simulation of DNA damage complexity from photons and protons.

Relative Biological Effectiveness (RBE), the ratio of doses between radiation modalities to produce the same biological endpoint, is a controversial and important topic in proton therapy. A number of phenomenological models incorporate variable RBE as a function of Linear Energy Transfer (LET), though a lack of mechanistic description limits their applicability. In this work we take a different approach, using a track structure model employing fundamental physics and chemistry to make predictions of proton and photon induced DNA damage, the first step in the mechanism of radiation-induced cell death. We apply this model to a proton therapy clinical case showing, for the first time, predictions of DNA damage on a patient treatment plan. Our model predictions are for an idealised cell and are applied to an ependymoma case, at this stage without any cell specific parameters. By comparing to similar predictions for photons, we present a voxel-wise RBE of DNA damage complexity. This RBE of damage complexity shows similar trends to the expected RBE for cell kill, implying that damage complexity is an important factor in DNA repair and therefore biological effect.

Comparing and Monitoring Risk-Adjusted Hospital Performance Measures: A Weighted Estimating Equations Approach.

Background. There is a great deal of interest in evaluating hospital performance in order to monitor and improve health care quality. Increasingly, risk-adjusted performance measures are available to the public and statistical approaches for estimating these measures are considered. Some methods in use currently are based on 3-year aggregates of data since a small number of cases may lead to imprecise estimates and make it hard for stakeholders to detect differences across hospitals over time. However, if quality changes over time, a measure based on these data is a biased estimate of present performance. Methods. We present an alternative approach (weighted estimating equations [WEE]) for combining historical data in estimation that regulates the tradeoff between bias and precision in the measure of present performance. The WEE approach uses all available historical data through estimating functions that down-weight past data. Results. We compare the WEE approach to two current practices using a realistic dataset of the mortality of patients following an elective percutaneous coronary intervention procedure in New York State who meet certain criteria. The width of the uncertainty interval in the realistic example is up to 65% smaller and the difference is more pronounced for hospitals with a small number of cases. Conclusions. The advantage of this approach extends from the example dataset to other datasets. The WEE approach uses all available data rather than data from an arbitrary 3-year window. The effect of borrowing strength from historical data is a more precise estimate of present performance than current practices. Its advantages are important for the comparison of other aspects of medical performance, including surgical or medical practitioner performance.

Image Guidance for Proton Therapy.

Image-guided radiotherapy has an established role in all forms of radiotherapy treatment delivery. Proton therapy seeks to deliver superior dose distributions through utilising the Bragg peak to target tumour and avoid sensitive normal tissue. The Bragg peak and sharp falloff in dose delivered by proton therapy necessitate careful treatment planning and treatment delivery. The dose distribution delivered by proton therapy is particularly sensitive to uncertainty in the prediction of proton range during treatment planning and deviations from the planned delivery during the course of the fractionated treatment. Realising the superior dose distribution of proton therapy requires increased diligence and image guidance has a key role in ensuring that treatments are planned and delivered. This article will outline the current status of image guidance for proton therapy, particularly highlighting differences with regard to high-energy X-ray therapy, and will look at a number of future improvements in image-guided proton therapy.

Aggregation of Markov flows I: theory.

A Markov flow is a stationary measure, with the associated flows and mean first passage times, for a continuous-time regular jump homogeneous semi-Markov process on a discrete state space. Nodes in the state space can be eliminated to produce a smaller Markov flow which is a factor of the original one. Some improvements to the elimination methods of Wales are given. The main contribution of the paper is to present an alternative, namely a method to aggregate groups of nodes to produce a factor. The method can be iterated to make hierarchical aggregation schemes. The potential benefits are efficient computation, including recomputation to take into account local changes, and insights into the macroscopic behaviour.This article is part of the theme issue 'Hilbert's sixth problem'.

In Silico Non-Homologous End Joining Following Ion Induced DNA Double Strand Breaks Predicts That Repair Fidelity Depends on Break Density.

This work uses Monte Carlo simulations to investigate the dependence of residual and misrepaired double strand breaks (DSBs) at 24 hours on the initial damage pattern created during ion therapy. We present results from a nanometric DNA damage simulation coupled to a mechanistic model of Non-Homologous End Joining, capable of predicting the position, complexity, and repair of DSBs. The initial damage pattern is scored by calculating the average number of DSBs within 70 nm from every DSB. We show that this local DSB density, referred to as the cluster density, can linearly predict misrepair regardless of ion species. The models predict that the fraction of residual DSBs is constant, with 7.3% of DSBs left unrepaired following 24 hours of repair. Through simulation over a range of doses and linear energy transfer (LET) we derive simple correlations capable of predicting residual and misrepaired DSBs. These equations are applicable to ion therapy treatment planning where both dose and LET are scored. This is demonstrated by applying the correlations to an example of a clinical proton spread out Bragg peak. Here we see a considerable biological effect past the distal edge, dominated by residual DSBs.

Abstract ID: 171 A Monte Carlo study to reduce range uncertainty in proton beam therapy via prompt gamma-ray detection.

In proton beam therapy precise knowledge of the proton beam range is essential to guarantee the treatment's efficacy and to avoid unnecessary toxicities. Unlike photon beams, protons stop inside the patient's body, therefore a direct detection of the distal fall-off is impossible. One technique to determine the beam range is to detect the prompt gamma (PG) rays emitted from the nuclei de-exciting following proton bombardment [1]. PG emission is almost instantaneous and has a high-production rate. The aim of this project is to develop a new method, based on an optimized PG detector system, which can achieve 3D range determination with an uncertainty of no more than 2 mm. The presented method is based on the detection of discrete gamma-rays. As a first step, the position reconstruction capability of the PG detector system was examined by means of Geant4 simulations. The prototype system is comprised of 12 LaBr3(Ce) detectors. The information recorded by each individual detector is fed into a reconstruction algorithm to determine the gamma-ray emission point in 3 dimensions. The development of the algorithm, proof-of-principle and simulation validation, have all been conducted using a sealed 60Co source. Our simulations demonstrate that an ideal detector system with the current reconstruction algorithm is capable of determining the source position with sub-millimetre accuracy. Having obtained proof-of-principle for the reconstruction algorithm the next stage is to investigate how implementing a realistic detector system affects the reconstruction performance. In addition, the ability of the detector system to discriminate between multiple sources in different positions is under evaluation.

Comparing heteroscedastic measurement systems with the probability of agreement.

Deciding whether two measurement systems agree well enough to be used interchangeably is important in medical and clinical contexts. Recently, the probability of agreement was proposed as an alternative to comparison techniques such as correlation, regression, and the limits of agreement approach, when the systems' measurement errors are homoscedastic. However, in medical and clinical contexts, it is common for measurement variability to increase proportionally with the magnitude of measurement. In this article, we extend the probability of agreement analysis to accommodate heteroscedastic measurement errors, demonstrating the versatility of this simple metric. We illustrate its use with two examples: one involving the comparison of blood pressure measurement devices, and the other involving the comparison of serum cholesterol assays.